A population-based cohort study of longitudinal change of high-density lipoprotein cholesterol impact on gastrointestinal cancer risk

High-density Lipoprotein Cholesterol (HDL-C) levels have been associated with cancer. In this observational population-based cohort study using data from the Korean National Health Insurance Service system, we investigate the impact of longitudinal changes in HDL-C levels on gastrointestinal cancer risk. Individuals who underwent health examinations in 2010 and 2014 were followed-up through 2021. Among 3.131 million, 40696 gastric, 35707 colorectal, 21309 liver, 11532 pancreatic, 4225 gallbladder, and 7051 biliary cancers are newly detected. The persistent low HDL-C group increases the risk of gastric, liver, and biliary cancer comparing to persistent normal HDL-C group. HDL-C change from normal to low level increases the risk for gastric, colorectal, liver, pancreatic, gallbladder, and biliary cancers. Effects of HDL-C change on the gastrointestinal cancer risk are also modified by sex and smoking status. HDL-C changes affect the gastric and gallbladder cancer risk in age ≥60 years and the pancreatic and biliary cancer risk in age <60 years. Here, we show persistently low HDL-C and normal-to-low HDL-C change increase gastrointestinal cancer risk with discrepancies by sex, smoking status, and age.


Supplementary Table 2. Gastrointestinal cancer risk by baseline HDL-C
*Adjusted for age, sex, body mass index, hypertension, diabetes, cerebrovascular disease, heart disease, smoking status, drinking status, LDL, TG, lipid lowering drug, and physical activity.† Liver factors (chronic hepatitis B, chronic hepatitis C, and liver cirrhosis) were additionally adjusted in liver cancer analysis.CI, confidence interval; HDL-C, high density lipoprotein cholesterol; HR, hazard ratio.
Low HDL-C refers to HDL-C < 40mg/dL in men and < 50mg/dL in women.Normal HDL-C means HDL-C ≥ 40mg/dL in men and ≥ 50mg/dL in women.

Table 4 . Sensitivity analysis II (Model III)
Adjusted for age, sex, economic status, body mass index, hypertension, diabetes, cerebrovascular disease, heart disease, smoking status, drinking status, physical activity, use of lipid lowering drug, liver factors (chronic liver disease, chronic hepatitis B, chronic hepatitis C, and liver cirrhosis) and triglyceride.* Adjusted for age, sex, economic status, body mass index, hypertension, diabetes, cerebrovascular disease, heart disease, smoking status, drinking status, physical activity, LDL, TG, and use of lipid lowering drug.CI, confidence interval; HDL-C, high density lipoprotein cholesterol; HR, hazard ratio.Low HDL-C refers to <40mg/dL in men and <50mg/dL in women.Normal HDL-C *means ≥40mg/dL in men and ≥50mg/dL in women.Exclusion any cancers up to 2 nd measurement of HDL-C Adjusted HRs and CIs are derived from Cox proportional regression analysis.All statistical tests are two-sided.Supplementary Table 5.

Interaction analysis (Joint test) Interaction between sex and HDL-C change in the cancer risk Interaction between smoking and HDL-C change in the cancer risk Interaction between age group and HDL-C change in the cancer risk
Supplementary Table 6.

Subgroup analysis by combination of sex and smoking status
Adjusted for sex, economic status, body mass index, hypertension, diabetes, cerebrovascular disease, heart disease, SMK, drinking status, physical activity, LDL, TG, and use of lipid lowering drug.†Adjusted for sex, economic status, body mass index, hypertension, diabetes, cerebrovascular disease, heart disease, SMK, drinking status, physical activity, LDL, TG, use of lipid lowering drug, liver factors (chronic liver disease, chronic hepatitis B, chronic hepatitis C, and liver cirrhosis) and triglyceride.Adjusted HRs and CIs are derived from Cox proportional regression analysis.All statistical tests are two-sided.

Table 7 . Gastrointestinal cancer risk by further categorization of HDL-C change
Adjusted HRs and CIs are derived from Cox proportional regression analysis.All statistical tests are two-sided.
*Adjusted for age, sex, economic status, body mass index, hypertension, diabetes, cerebrovascular disease, heart disease, smoking status, drinking status, physical activity, LDL, TG, and use of lipid lowering drug.†Adjustedfor age, sex, economic status, body mass index, hypertension, diabetes, cerebrovascular disease, heart disease, smoking status, drinking status, physical activity, LDL, TG, use of lipid lowering drug, and liver factors (chronic liver disease, chronic hepatitis B, chronic hepatitis C, and liver cirrhosis).CI, confidence interval; HDL-C, high density lipoprotein cholesterol; HR, hazard ratio.Low HDL-C refers to <40mg/dL in men and <50mg/dL in women.Normal HDL-C means ≥40mg/dL in men and ≥50mg/dL in women.Increase means∆HDL-C [(HDL-C at follow-up) -(HDL-C baseline)] ≥ 15mg/dL.Detail definition was provided in Fig 1C and Method.

Table 8 . Gastrointestinal cancer risk by absolute HDL-C change
Adjusted for age, sex, economic status, body mass index, hypertension, diabetes, cerebrovascular disease, heart disease, smoking status, drinking status, physical activity, use of lipid lowering drug, LDL, TG, and liver factors (chronic liver disease, chronic hepatitis B, chronic hepatitis C, and liver cirrhosis).* Adjusted for age, sex, economic status, body mass index, hypertension, diabetes, cerebrovascular disease, heart disease, smoking status, drinking status, physical activity, -significance.∆HDL-C = (HDL-C at follow-up) -(HDL-C at baseline). *